title: Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism.
abstract: Glutamate receptor interacting protein 1 (GRIP1) is a neuronal scaffolding protein that interacts directly with the C termini of glutamate receptors 2/3 (GluA2/3) via its PDZ domains 4 to 6 (PDZ4-6). We found an association (P<0.05) of a SNP within the PDZ4-6 genomic region with autism by genotyping autistic patients (n=480) and matched controls (n=480). Parallel sequencing identified five rare missense variants within or near PDZ4-6 only in the autism cohort, resulting in a higher cumulative mutation load (P=0.032). Two variants correlated with a more severe deficit in reciprocal social interaction in affected sibling pairs from proband families. These variants were associated with altered interactions with GluA2/3 and faster recycling and increased surface distribution of GluA2 in neurons, suggesting gain-of-function because GRIP1/2 deficiency showed opposite phenotypes. Grip1/2 knockout mice exhibited increased sociability and impaired prepulse inhibition. These results support a role for GRIP in social behavior and implicate GRIP1 variants in modulating autistic phenotype.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, The Howard Hughes Medical Institute, Predoctoral Training Program in Human Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Mejias
authors.forename: Abby
authors.initials: A
authors.lastname: Adamczyk
authors.forename: Victor
authors.initials: V
authors.lastname: Anggono
authors.forename: Tejasvi
authors.initials: T
authors.lastname: Niranjan
authors.forename: Gareth M
authors.initials: GM
authors.lastname: Thomas
authors.forename: Kamal
authors.initials: K
authors.lastname: Sharma
authors.forename: Cindy
authors.initials: C
authors.lastname: Skinner
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Roger E
authors.initials: RE
authors.lastname: Stevenson
authors.forename: M Daniele
authors.initials: MD
authors.lastname: Fallin
authors.forename: Walter
authors.initials: W
authors.lastname: Kaufmann
authors.forename: Mikhail
authors.initials: M
authors.lastname: Pletnikov
authors.forename: David
authors.initials: D
authors.lastname: Valle
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D015331:Cohort Studies; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D051381:Rats; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C491310:GRIP1 protein, human; C491309:Grip1 protein, mouse; C491308:Grip1 protein, rat; C485567:Grip2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D017470:Receptors, Glutamate